Schizophrenia (SCZ) is a generally devastating neuropsychiatric illness with considerable morbidity, mortality, and personal and societal cost. Genetic factors have been strongly implicated via family and twin data, and more recently directly through genome-wide association studies (GWAS) and sequencing studies. Epigenetic modifications play a well-accepted role in a variety of medical and neurological illnesses, and are also implicated in SCZ. Somatic mosaicism is an underexplored, but potentially very important contributor to SCZ. There have been some intriguing hints that somatic mosaicism may play a role in SCZ, but assessment of this possibility awaits rigorous experiments, and that is the overarching goal of this proposal. The primary objective of our project is to identify and characterize the extent of somatic variation in post-mortem human brain samples from individuals with SCZ and controls. Following on work of members of our team, we will rigorously assess the somatic mosaicism in a large cohort of post-mortem human brains from the Common Mind Consortium, which members of our group are already analyzing for genotype, mRNA-seq and epigenome mapping. These brains are from individuals with SCZ (250) and controls (50+). We will look for retrotransposition events, copy number variants (CNVs) and single nucleotide variants (SNVs). All data will be made available to the research community through the Sage Bionetworks Synapse Platform. We have assembled the critical personnel, sample resources, technological know-how, and analytic strategies to be able to assess the role of somatic variation in the brain as well as begin to unravel SCZ biology.